Abstract:

This invention relates to novel azabicyclo[3.2.1]oct-2-ene derivatives
useful as monoamine neurotransmitter re-uptake inhibitors.
In other aspects the invention relates to the use of these compounds in a
method for therapy and to pharmaceutical compositions comprising the
compounds of the invention.

Claims:

1. A compound of Formula I: ##STR00004## any of its stereoisomers or any
mixture of its stereoisomers,or a pharmaceutically acceptable salt
thereof;whereinR represents hydrogen or alkyl;which alkyl is optionally
substituted with one or more substituents independently selected from the
group consisting of:halo, trifluoromethyl, trifluoromethoxy, cyano,
hydroxy, amino, nitro, alkoxy, cycloalkoxy, alkyl, cycloalkyl,
cycloalkylalkyl, alkenyl and alkynyl;Ra represents alkyl; andRb
represents halo, trifluoromethyl, trifluoromethoxy, cyano, nitro,
hydroxy, alkoxy, cycloalkoxy, alkoxyalkyl, cycloalkoxyalkyl, alkyl,
cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, --NR'R'',
--(C═O)NR'R'' or --NR'(C═O)R'';wherein R' and R'' independent of
each other are hydrogen or alkyl.

6. The compound of claim 1 being a compound of Formula II ##STR00005## any
of its stereoisomers or any mixture of its stereoisomers,or a
pharmaceutically acceptable salt thereof;whereinR is as defined in claim
1;one of Ro, Rm and Rp represents Ra;one of the
remaining two of Ro, Rm and Rp represents Rb; andthe
remaining one of Ro, Rm and Rp represents hydrogen;wherein
Ra and Ra are as defined in claim 1.

8. A pharmaceutical composition, comprising a therapeutically effective
amount of a compound of claim 1, any of its stereoisomers or any mixture
of its stereoisomers, or a pharmaceutically acceptable salt thereof,
together with at least one pharmaceutically acceptable carrier, excipient
or diluent.

10. A method for treatment, prevention or alleviation of a disease or a
disorder or a condition of a living animal body, including a human, which
disorder, disease or condition is responsive to inhibition of monoamine
neurotransmitter re-uptake in the central nervous system, which method
comprises the step of administering to such a living animal body in need
thereof a therapeutically effective amount of a compound according to
claim 1, any of its stereoisomers or any mixture of its stereoisomers, or
a pharmaceutically acceptable salt thereof.

Description:

[0002]In other aspects the invention relates to the use of these compounds
in a method for therapy and to pharmaceutical compositions comprising the
compounds of the invention.

BACKGROUND ART

[0003]Serotonin Selective Reuptake Inhibitors (SSRIs) currently provide
efficacy in the treatment of several CNS disorders, including depression
and panic disorder. SSRIs are generally perceived by psychiatrists and
primary care physicians as effective, well-tolerated and easily
administered. However, they are associated with a number of undesirable
features.

[0004]Thus, there is still a strong need for compounds with an optimised
pharmacological profile as regards the activity on reuptake of the
monoamine neurotransmitters serotonin, dopamine and noradrenaline, such
as the ratio of the serotonin reuptake versus the noradrenaline and
dopamine reuptake activity.

SUMMARY OF THE INVENTION

[0005]In its first aspect, the invention provides a compound of Formula I:

##STR00001##

any of its isomers or any mixture of its isomers, or a pharmaceutically
acceptable salt thereof,wherein R, Ra and Rb are as defined
below.

[0006]In its second aspect, the invention provides a pharmaceutical
composition, comprising a therapeutically effective amount of a compound
of the invention, any of its isomers or any mixture of its isomers, or a
pharmaceutically acceptable salt thereof, together with at least one
pharmaceutically acceptable carrier, excipient or diluent.

[0007]In a further aspect, the invention provides the use of a compound of
the invention, any of its isomers or any mixture of its isomers, or a
pharmaceutically acceptable salt thereof, for the manufacture of a
pharmaceutical composition for the treatment, prevention or alleviation
of a disease or a disorder or a condition of a mammal, including a human,
which disease, disorder or condition is responsive to inhibition of
monoamine neurotransmitter re-uptake in the central nervous system.

[0008]In a still further aspect, the invention relates to a method for
treatment, prevention or alleviation of a disease or a disorder or a
condition of a living animal body, including a human, which disorder,
disease or condition is responsive to inhibition of monoamine
neurotransmitter re-uptake in the central nervous system, which method
comprises the step of administering to such a living animal body in need
thereof a therapeutically effective amount of a compound of the
invention, any of its isomers or any mixture of its isomers, or a
pharmaceutically acceptable salt thereof.

[0009]Other objects of the invention will be apparent to the person
skilled in the art from the following detailed description and examples.

DETAILED DISCLOSURE OF THE INVENTION

Azabicyclo[3.2.1]oct-2-ene derivatives

[0010]In its first aspect the present invention provides compounds of
Formula I:

[0017]In a special embodiment, Rb represents halo or alkyl. In a
further embodiment, Rb represents halo such as bromo, chloro or
fluoro. In a still further embodiment, Rb represents alkyl, such as
methyl.

[0018]In a still further embodiment, the invention provides compounds of
Formula II

##STR00003##

any of its isomers or any mixture of its isomers,or a pharmaceutically
acceptable salt thereof;whereinR is as defined above;one of Ro,
Rm and Rp represents Ra;one of the remaining two of
Ro, Rm and Rp represents Rb; andthe remaining one of
Ro, Rm and Rp represents hydrogen;

[0019]wherein Ra and Ra are as defined above.

[0020]In a special embodiment, Ro represents hydrogen, Rm
represents Ra and Rp represents Rb. In a further
embodiment, Ro represents hydrogen, Rm represents Rb and
Rp represents Ra. In a still further embodiment, Rp
represents hydrogen, Rm represents Ra and Ro represents
Rb. In a further embodiment, Rp represents hydrogen,

[0049]Any combination of two or more of the embodiments as described above
is considered within the scope of the present invention.

Definition of Substituents

[0050]In the context of this invention halo represents fluoro, chloro,
bromo or iodo.

[0051]In the context of this invention an alkyl group designates a
univalent saturated, straight or branched hydrocarbon chain. The
hydrocarbon chain preferably contains of from one to six carbon atoms
(C1-6-alkyl), including pentyl, isopentyl, neopentyl, tertiary
pentyl, hexyl and isohexyl. In a preferred embodiment alkyl represents a
C1-4-alkyl group, including butyl, isobutyl, secondary butyl, and
tertiary butyl. In another preferred embodiment of this invention alkyl
represents a C1-3-alkyl group, which may in particular be methyl,
ethyl, propyl or isopropyl.

[0052]In the context of this invention an alkenyl group designates a
carbon chain containing one or more double bonds, including di-enes,
tri-enes and poly-enes. In a preferred embodiment the alkenyl group of
the invention comprises of from two to six carbon atoms
(C2-6-alkenyl), including at least one double bond. In a most
preferred embodiment the alkenyl group of the invention is ethenyl; 1- or
2-propenyl; 1-, 2- or 3-butenyl, or 1,3-butadienyl; 1-, 2-, 3-, 4- or
5-hexenyl, or 1,3-hexadienyl, or 1,3,5-hexatrienyl.

[0053]In the context of this invention an alkynyl group designates a
carbon chain containing one or more triple bonds, including di-ynes,
tri-ynes and poly-ynes. In a preferred embodiment the alkynyl group of
the invention comprises of from two to six carbon atoms
(C2-6-alkynyl), including at least one triple bond. In its most
preferred embodiment the alkynyl group of the invention is ethynyl; 1-,
or 2-propynyl; 1-, 2-, or 3-butynyl, or 1,3-butadiynyl; 1-, 2-, 3-,
4-pentynyl, or 1,3-pentadiynyl; 1-, 2-, 3-, 4-, or 5-hexynyl, or
1,3-hexadiynyl or 1,3,5-hexatriynyl.

[0054]In the context of this invention a cycloalkyl group designates a
cyclic alkyl group, preferably containing of from three to seven carbon
atoms (C3-7-cycloalkyl), including cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl and cycloheptyl.

[0057]Cycloalkylalkyl means cycloalkyl as above and alkyl as above,
meaning for example, cyclopropylmethyl.

Pharmaceutically Acceptable Salts

[0058]The chemical compound of the invention may be provided in any form
suitable for the intended administration. Suitable forms include
pharmaceutically (i.e. physiologically) acceptable salts, and pre- or
prodrug forms of the chemical compound of the invention.

[0059]Examples of pharmaceutically acceptable addition salts include,
without limitation, the non-toxic inorganic and organic acid addition
salts such as the hydro-chloride, the hydrobromide, the nitrate, the
perchlorate, the phosphate, the sulphate, the formate, the acetate, the
aconate, the ascorbate, the benzenesulphonate, the benzoate, the
cinnamate, the citrate, the embonate, the enantate, the fumarate, the
glutamate, the glycolate, the lactate, the maleate, the malonate, the
mandelate, the methanesulphonate, the naphthalene-2-sulphonate, the
phthalate, the salicylate, the sorbate, the stearate, the succinate, the
tartrate, the toluene-p-sulphonate, and the like. Such salts may be
formed by procedures well known and described in the art.

[0060]Other acids such as oxalic acid, which may not be considered
pharmaceutically acceptable, may be useful in the preparation of salts
useful as intermediates in obtaining a chemical compound of the invention
and its pharmaceutically acceptable acid addition salt.

[0061]Examples of pharmaceutically acceptable cationic salts of a chemical
compound of the invention include, without limitation, the sodium, the
potassium, the calcium, the magnesium, the zinc, the aluminium, the
lithium, the choline, the lysinium, and the ammonium salt, and the like,
of a chemical compound of the invention containing an anionic group. Such
cationic salts may be formed by procedures well known and described in
the art.

[0062]In the context of this invention the "onium salts" of N-containing
compounds are also contemplated as pharmaceutically acceptable salts.
Preferred "onium salts" include the alkyl-onium salts, the
cycloalkyl-onium salts, and the cycloalkylalkyl-onium salts.

[0063]Examples of pre- or prodrug forms of the chemical compound of the
invention include examples of suitable prodrugs of the substances
according to the invention include compounds modified at one or more
reactive or derivatizable groups of the parent compound. Of particular
interest are compounds modified at a carboxyl group, a hydroxyl group, or
an amino group. Examples of suitable derivatives are esters or amides.

[0064]The chemical compound of the invention may be provided in dissoluble
or indissoluble forms together with a pharmaceutically acceptable solvent
such as water, ethanol, and the like. Dissoluble forms may also include
hydrated forms such as the monohydrate, the dihydrate, the hemihydrate,
the trihydrate, the tetrahydrate, and the like. In general, the
dissoluble forms are considered equivalent to indissoluble forms for the
purposes of this invention.

Steric Isomers

[0065]It will be appreciated by those skilled in the art that the
compounds of the present invention may exist in different stereoisomeric
forms--including enantiomers, diastereomers and cis-trans-isomers.

[0066]The invention includes all such isomers and any mixtures thereof
including racemic mixtures.

[0067]Racemic forms can be resolved into the optical antipodes by known
methods and techniques. One way of separating the enantiomeric compounds
(including enantiomeric intermediates) is--in the case the compound being
a chiral acid--by use of an optically active amine, and liberating the
diastereomeric, resolved salt by treatment with an acid. Another method
for resolving racemates into the optical antipodes is based upon
chromatography on an optical active matrix. Racemic compounds of the
present invention can thus be resolved into their optical antipodes,
e.g., by fractional crystallisation of D- or L- (tartrates, mandelates,
or camphorsulphonate) salts for example.

[0068]The chemical compounds of the present invention may also be resolved
by the formation of diastereomeric amides by reaction of the chemical
compounds of the present invention with an optically active activated
carboxylic acid such as that derived from (+) or (-) phenylalanine, (+)
or (-) phenylglycine, (+) or (-) camphanic acid or by the formation of
diastereomeric carbamates by reaction of the chemical compound of the
present invention with an optically active chloroformate or the like.

[0069]Additional methods for the resolving the optical isomers are known
in the art. Such methods include those described by Jaques J, Collet A, &
Wilen S in "Enantiomers, Racemates, and Resolutions", John Wiley and
Sons, New York (1981).

[0070]Optical active compounds can also be prepared from optical active
starting materials or intermediates.

Labelled Compounds

[0071]The compounds of the invention may be used in their labelled or
unlabelled form. In the context of this invention the labelled compound
has one or more atoms replaced by an atom having an atomic mass or mass
number different from the atomic mass or mass number usually found in
nature. The labelling will allow easy quantitative detection of said
compound.

[0072]The labelled compounds of the invention may be useful as diagnostic
tools, radio tracers, or monitoring agents in various diagnostic methods,
and for in vivo receptor imaging.

[0073]The labelled isomer of the invention preferably contains at least
one radio-nuclide as a label. Positron emitting radionuclides are all
candidates for usage. In the context of this invention the radionuclide
is preferably selected from 2H (deuterium), 3H (tritium),
13C, 14C, 131I, 125I, 123I, and 18F.

[0075]The chemical compounds of the invention may be prepared by
conventional methods for chemical synthesis, e.g. those described in the
working examples. The starting materials for the processes described in
the present application are known or may readily be prepared by
conventional methods from commercially available chemicals.

[0076]Also one compound of the invention can be converted to another
compound of the invention using conventional methods.

[0077]The end products of the reactions described herein may be isolated
by conventional techniques, e.g. by extraction, crystallisation,
distillation, chromatography, etc.

Biological Activity

[0078]Compounds of the invention may be tested for their ability to
inhibit reuptake of the monoamines dopamine, noradrenaline and serotonin
in synaptosomes e.g. such as described in WO 97/30997. Based on the
balanced activity observed in these tests the compound of the invention
is considered useful for the treatment, prevention or alleviation of a
disease or a disorder or a condition of a mammal, including a human,
which disease, disorder or condition is responsive to inhibition of
monoamine neurotransmitter re-uptake in the central nervous system.

[0080]It is at present contemplated that a suitable dosage of the active
pharmaceutical ingredient (API) is within the range of from about 0.1 to
about 1000 mg API per day, more preferred of from about 10 to about 500
mg API per day, most preferred of from about 30 to about 100 mg API per
day, dependent, however, upon the exact mode of administration, the form
in which it is administered, the indication considered, the subject and
in particular the body weight of the subject involved, and further the
preference and experience of the physician or veterinarian in charge.
Preferred compounds of the invention show a biological activity in the
sub-micromolar and micromolar range, i.e. of from below 1 to about 100
μM.

Pharmaceutical Compositions

[0081]In another aspect the invention provides novel pharmaceutical
compositions comprising a therapeutically effective amount of the
chemical compound of the invention.

[0082]While a chemical compound of the invention for use in therapy may be
administered in the form of the raw chemical compound, it is preferred to
introduce the active ingredient, optionally in the form of a
physiologically acceptable salt, in a pharmaceutical composition together
with one or more adjuvants, excipients, carriers, buffers, diluents,
and/or other customary pharmaceutical auxiliaries.

[0083]In a preferred embodiment, the invention provides pharmaceutical
compositions comprising the chemical compound of the invention, or a
pharmaceutically acceptable salt or derivative thereof, together with one
or more pharmaceutically acceptable carriers, and, optionally, other
therapeutic and/or prophylactic ingredients, known and used in the art.
The carrier(s) must be "acceptable" in the sense of being compatible with
the other ingredients of the formulation and not harmful to the recipient
thereof.

[0084]Pharmaceutical compositions of the invention may be those suitable
for oral, rectal, bronchial, nasal, pulmonal, topical (including buccal
and sub-lingual), transdermal, vaginal or parenteral (including
cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous,
intraarterial, intracerebral, intraocular injection or infusion)
administration, or those in a form suitable for administration by
inhalation or insufflation, including powders and liquid aerosol
administration, or by sustained release systems. Suitable examples of
sustained release systems include semipermeable matrices of solid
hydrophobic polymers containing the compound of the invention, which
matrices may be in form of shaped articles, e.g. films or microcapsules.

[0085]The chemical compound of the invention, together with a conventional
adjuvant, carrier, or diluent, may thus be placed into the form of
pharmaceutical compositions and unit dosages thereof. Such forms include
solids, and in particular tablets, filled capsules, powder and pellet
forms, and liquids, in particular aqueous or non-aqueous solutions,
suspensions, emulsions, elixirs, and capsules filled with the same, all
for oral use, suppositories for rectal administration, and sterile
injectable solutions for parenteral use. Such pharmaceutical compositions
and unit dosage forms thereof may comprise conventional ingredients in
conventional proportions, with or without additional active compounds or
principles, and such unit dosage forms may contain any suitable effective
amount of the active ingredient commensurate with the intended daily
dosage range to be employed.

[0086]The chemical compound of the present invention can be administered
in a wide variety of oral and parenteral dosage forms. It will be obvious
to those skilled in the art that the following dosage forms may comprise,
as the active component, either a chemical compound of the invention or a
pharmaceutically acceptable salt of a chemical compound of the invention.

[0087]For preparing pharmaceutical compositions from a chemical compound
of the present invention, pharmaceutically acceptable carriers can be
either solid or liquid.

[0088]Solid form preparations include powders, tablets, pills, capsules,
cachets, suppositories, and dispersible granules. A solid carrier can be
one or more substances which may also act as diluents, flavouring agents,
solubilizers, lubricants, suspending agents, binders, preservatives,
tablet disintegrating agents, or an encapsulating material.

[0089]In powders, the carrier is a finely divided solid, which is in a
mixture with the finely divided active component.

[0090]In tablets, the active component is mixed with the carrier having
the necessary binding capacity in suitable proportions and compacted in
the shape and size desired.

[0091]The powders and tablets preferably contain from five or ten to about
seventy percent of the active compound. Suitable carriers are magnesium
carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,
starch, gelatin, tragacanth, methylcellulose, sodium
carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
The term "preparation" is intended to include the formulation of the
active compound with encapsulating material as carrier providing a
capsule in which the active component, with or without carriers, is
surrounded by a carrier, which is thus in association with it. Similarly,
cachets and lozenges are included. Tablets, powders, capsules, pills,
cachets, and lozenges can be used as solid forms suitable for oral
administration.

[0092]For preparing suppositories, a low melting wax, such as a mixture of
fatty acid glyceride or cocoa butter, is first melted and the active
component is dispersed homogeneously therein, as by stirring. The molten
homogenous mixture is then poured into convenient sized moulds, allowed
to cool, and thereby to solidify.

[0093]Compositions suitable for vaginal administration may be presented as
pessaries, tampons, creams, gels, pastes, foams or sprays containing in
addition to the active ingredient such carriers as are known in the art
to be appropriate.

[0094]Liquid preparations include solutions, suspensions, and emulsions,
for example, water or water-propylene glycol solutions. For example,
parenteral injection liquid preparations can be formulated as solutions
in aqueous polyethylene glycol solution.

[0095]The chemical compound according to the present invention may thus be
formulated for parenteral administration (e.g. by injection, for example
bolus injection or continuous infusion) and may be presented in unit dose
form in ampoules, pre-filled syringes, small volume infusion or in
multi-dose containers with an added preservative. The compositions may
take such forms as suspensions, solutions, or emulsions in oily or
aqueous vehicles, and may contain formulation agents such as suspending,
stabilising and/or dispersing agents. Alternatively, the active
ingredient may be in powder form, obtained by aseptic isolation of
sterile solid or by lyophilization from solution, for constitution with a
suitable vehicle, e.g. sterile, pyrogen-free water, before use.

[0096]Aqueous solutions suitable for oral use can be prepared by
dissolving the active component in water and adding suitable colorants,
flavours, stabilising and thickening agents, as desired.

[0097]Aqueous suspensions suitable for oral use can be made by dispersing
the finely divided active component in water with viscous material, such
as natural or synthetic gums, resins, methylcellulose, sodium
carboxymethylcellulose, or other well known suspending agents.

[0098]Also included are solid form preparations, intended for conversion
shortly before use to liquid form preparations for oral administration.
Such liquid forms include solutions, suspensions, and emulsions. In
addition to the active component such preparations may comprise
colorants, flavours, stabilisers, buffers, artificial and natural
sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0099]For topical administration to the epidermis the chemical compound of
the invention may be formulated as ointments, creams or lotions, or as a
transdermal patch. Ointments and creams may, for example, be formulated
with an aqueous or oily base with the addition of suitable thickening
and/or gelling agents. Lotions may be formulated with an aqueous or oily
base and will in general also contain one or more emulsifying agents,
stabilising agents, dispersing agents, suspending agents, thickening
agents, or colouring agents.

[0100]Compositions suitable for topical administration in the mouth
include lozenges comprising the active agent in a flavoured base, usually
sucrose and acacia or tragacanth; pastilles comprising the active
ingredient in an inert base such as gelatin and glycerine or sucrose and
acacia; and mouthwashes comprising the active ingredient in a suitable
liquid carrier.

[0101]Solutions or suspensions are applied directly to the nasal cavity by
conventional means, for example with a dropper, pipette or spray. The
compositions may be provided in single or multi-dose form.

[0102]Administration to the respiratory tract may also be achieved by
means of an aerosol formulation in which the active ingredient is
provided in a pressurised pack with a suitable propellant such as a
chlorofluorocarbon (CFC) for example dichlorodifluoromethane,
trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or
other suitable gas. The aerosol may conveniently also contain a
surfactant such as lecithin. The dose of drug may be controlled by
provision of a metered valve.

[0103]Alternatively the active ingredients may be provided in the form of
a dry powder, for example a powder mix of the compound in a suitable
powder base such as lactose, starch, starch derivatives such as
hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
Conveniently the powder carrier will form a gel in the nasal cavity. The
powder composition may be presented in unit dose form for example in
capsules or cartridges of, e.g., gelatin, or blister packs from which the
powder may be administered by means of an inhaler.

[0104]In compositions intended for administration to the respiratory
tract, including intranasal compositions, the compound will generally
have a small particle size for example of the order of 5 microns or less.
Such a particle size may be obtained by means known in the art, for
example by micronization.

[0105]When desired, compositions adapted to give sustained release of the
active ingredient may be employed.

[0106]The pharmaceutical preparations are preferably in unit dosage forms.
In such form, the preparation is subdivided into unit doses containing
appropriate quantities of the active component. The unit dosage form can
be a packaged preparation, the package containing discrete quantities of
preparation, such as packaged tablets, capsules, and powders in vials or
ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or
lozenge itself, or it can be the appropriate number of any of these in
packaged form.

[0107]Tablets or capsules for oral administration and liquids for
intravenous administration and continuous infusion are preferred
compositions.

[0108]Further details on techniques for formulation and administration may
be found in the latest edition of Remington's Pharmaceutical Sciences
(Maack Publishing Co., Easton, Pa.).

[0109]A therapeutically effective dose refers to that amount of active
ingredient, which ameliorates the symptoms or condition. Therapeutic
efficacy and toxicity, e.g. ED50 and LD50, may be determined by
standard pharmacological procedures in cell cultures or experimental
animals. The dose ratio between therapeutic and toxic effects is the
therapeutic index and may be expressed by the ratio LD50/ED50.
Pharmaceutical compositions exhibiting large therapeutic indexes are
preferred.

[0110]The dose administered must of course be carefully adjusted to the
age, weight and condition of the individual being treated, as well as the
route of administration, dosage form and regimen, and the result desired,
and the exact dosage should of course be determined by the practitioner.

[0111]The actual dosage depends on the nature and severity of the disease
being treated, and is within the discretion of the physician, and may be
varied by titration of the dosage to the particular circumstances of this
invention to produce the desired therapeutic effect. However, it is
presently contemplated that pharmaceutical compositions containing of
from about 0.1 to about 500 mg of active ingredient per individual dose,
preferably of from about 1 to about 100 mg, most preferred of from about
1 to about 10 mg, are suitable for therapeutic treatments.

[0112]The active ingredient may be administered in one or several doses
per day. A satisfactory result can, in certain instances, be obtained at
a dosage as low as 0.1 μg/kg i.v. and 1 μg/kg p.o. The upper limit
of the dosage range is presently considered to be about 10 mg/kg i.v. and
100 mg/kg p.o. Preferred ranges are from about 0.1 μg/kg to about 10
mg/kg/day i.v., and from about 1 μg/kg to about 100 mg/kg/day p.o.

Methods of Therapy

[0113]In another aspect the invention provides a method for the treatment,
prevention or alleviation of a disease or a disorder or a condition of a
living animal body, including a human, which disease, disorder or
condition is responsive to inhibition of monoamine neurotransmitter
re-uptake in the central nervous system, and which method comprises
administering to such a living animal body, including a human, in need
thereof an effective amount of a chemical compound of the invention.

[0114]It is at present contemplated that suitable dosage ranges are 0.1 to
1000 milligrams daily, 10-500 milligrams daily, and especially 30-100
milligrams daily, dependent as usual upon the exact mode of
administration, form in which administered, the indication toward which
the administration is directed, the subject involved and the body weight
of the subject involved, and further the preference and experience of the
physician or veterinarian in charge.

EXAMPLES

[0115]The invention is further illustrated with reference to the following
examples, which are not intended to be in any way limiting to the scope
of the invention as claimed.

[0116]General: All reactions involving air sensitive reagents or
intermediates were performed under nitrogen and in anhydrous solvents.
Magnesium sulphate was used as drying agent in the workup-procedures and
solvents were evaporated under reduced pressure.

[0131]A mixture of 5-bromo-2-chlorotoluene (10.0 g, 48.7 mmol) in
diethylether (100 ml) was cooled to -70° C. followed by addition
of buthyllithium (21.4 ml, 2.5 M) at -70° C. The mixture was
stirred at room temperature for 1 h followed by addition of tropinone
(6.77 g, 48.7 mmol) at -70° C., solved in THF. The mixture was
stirred at -70° C. for 1 h. The mixture was allowed to warm to
room temperature. The mixture was made acidic by adding aqueous
hydrochloric acid (1 M). The acidic aqueous phase was washed with
diethylether (50 ml). The mixture was made alkaline by adding aqueous
sodium hydroxide followed by extraction with diethylether (3×50
ml). Yield of intermediate
(±)-3-(4-chloro-3-methyl-phenyl)-8-methyl-8-aza-bicyclo[3.2.1]octan-3--
ol 11.6 g (90%). A mixture of
(+/-)-3-(4-chloro-3-methyl-phenyl)-8-methyl-8-aza-bicyclo[3.2.1]octan-3-o-
l (7.5 g, 28.2 mmol) and aqueous hydrogen chloride (37%) was stirred at
reflux for 1 h. The mixture was allowed to cool to room temperature and
was made alkaline by adding concentrated aqueous ammonia. Yield 6.0 g
(86%). The hydrochloric salt was precipitated. Mp 177-179° C.

[0146]To a stirred mixture of [S--(R*,
R*)](-)-bis-alpha-methyl-benzylamine hydrochloric acid salt
([α]D25=(-) 73.2° (86.5 g, 0.33 mmol) and
tetrahydrofuran (1000 ml) was added at <5° C.: butyllithium
(264 ml, 2.5 M). The mixture was stirred at 0° C. for 1 h. The
mixture was cooled to -70° C. and tropinone (41.8 g, 0.3 mmol)
solved in tetrahydrofuran (200 ml) was added over a period of 90 min. The
mixture was stirred for 3 h at -70° C.
N-phenylbis-trifluoromethanesulfonimid (114.3 g, 0.32 mmol) solved in
tetrahydrofuran was added to the mixture <70° C. over 2 h time
period. The mixture was allowed to reach room temperature over night.
Water (3 L) was added followed by extraction with diethylether (2×1
L). The organic phase was washed with water (2×1 L). The crude
mixture of the title product and the chiral amine was separated by silica
gel (1 kg) column chromatography using ethyl acetate initially in order
to eluate the chiral amine and then use a mixture of methanol and
dichloromethane (2:8) for the chiral triflate. The chiral triflate was
isolated in 78% (0.233 mol).

[0148]A number of compounds were tested for their ability to inhibit the
reuptake of the monoamine neurotransmitters dopamine (DA) noradrenaline
(NA) and serotonine (5-HT) in synaptosomes as described in WO 97/16451.

[0149]The test values are given as IC50 (the concentration (μM) of
the test substance which inhibits the specific binding of 3H-DA,
3H-NA, or 3H-5-HT by 50%).

[0150]Test results obtained by testing selected compounds of the present
invention appear from the below table: